The present invention relates to the field of diagnostic imaging and more specifically to the field of monitoring drug delivery using non-invasive imaging techniques.
Multiple contrast agents are available for enhancing tissue contrast in magnetic resonance Imaging. Some of the most commonly used contrast agents are chelates of Gadolinium, such as Gd-DTPA, Gd-DTPA-BMA, and Gd-DOTA. Most currently available contrast agent formulations are of small molecular size. In imaging the brain, small molecular contrast agents will not cross the normal, intact blood brain barrier. Contrast enhancement is only seen in pathologic regions with disturbance or disruption of the blood brain barrier.
In imaging the body, however, no barrier with functions similar to those of the blood-brain-barrier exists except for the ovary and testicles. All clinically available small molecular agents will cross the endothelial membrane easily and will be rapidly excreted by the kidney. Thus, with small molecular contrast agents, enhancement will be observed with both pathologic, as well as normal, tissue. Macromolecules of sufficient size, however, will not permeate normal endothelium unless they are taken up by the reticuloendothelial system. Only when capillary permeability is increased, as it is the case with tumors, can such macromolecules extravasate through the endothelial membrane and accumulate in the tissue, e.g. tumor tissue.
Several prototype macromolecular MR contrast agents agents have been developed such as Gd-DTPA bound to albumin (see Brasch xe2x80x9cRationale and applications for macromolecular Gd-based contrast agentsxe2x80x9d Magn Res Med, 22, 282-287, (1991)), Gd-DTPA bound to carbohydrates (see Klaveness, et al. xe2x80x9cA diagnostic agent containing a non-radioactive paramagnetic metal species in a macromolecular carrierxe2x80x9d United States Patent, (1991)), and Gd-chelates bound to polylysine. While all of these agents hold the potential to be used as macromolecular contrast agents in-vivo in human subjects, they are hampered by multiple problems. Albumin-Gd-DTPA, for example, suffers from significant antigenicity (see Brasch xe2x80x9cRationale and applications for macromolecular Gd-based contrast agentsxe2x80x9d Magn Res Med, 22, 282-287, (1991)) and anaphylactic reaction may occur after injection. Inadequate size is another problem. If the compound is too large, it will not extravasate through the endothelial membrane. If the compound is too small, it may again permeate into normal rather than pathologic tissues only. Finally, renal or hepatic excretion of the macromolecular compounds is often Insufficient for clinical use (see Brasch xe2x80x9cRationale and applications for macromolecular Gd-based contrast agentsxe2x80x9d Magn Res Med, 22, 282-287, (1991)).
The present invention provides for imaging agents that selectively target pathologic or cancerous tissues compared with normal or non-cancerous tissues with use of liposomes with prolonged circulation time and discloses the use of such formulations for monitoring delivery of therapeutic agents or drugs to a lesion such as a tumor.
The present invention provides for imaging agents and compositions useful for NMR, scintigraphy, PET and any other type of imaging where the imaging agent can be carried by liposomes. Generally, the imaging composition comprises an imaging agent, with a liposome with an agent that increases blood circulation life time and a therapeutic agent that is selected for a particular type of treatment or tissue, such as cancer or tissues with increased capillary permeability. For instance, the invention provides for a composition for NMR imaging during drug delivery, comprising:
a) a paramagnetic chelate with a paramagnetic ion and in amount sufficient to enhance NMR imaging,
b) a liposome comprising a bilayer and an interior volume, wherein said liposome is in an amount sufficient to permit selective delivery of said liposome to a tissue compared to delivery in the absence of said liposome, and said liposome carries said paramagnetic chelate,
c) a polyalkylether associated with said liposome, and
d) a therapeutic agent in an therapeutic amount, wherein said liposome carries said therapeutic agent.